6 JANUARY 2017 • VOL 355 ISSUE 6320 29 SCIENCE sciencemag.org
imposing some of these constraints in the
development of functionals often produces
better electron densities (1, 9). As Medvedev
et al. show, this strategy improves accuracy
of both the energies and densities of atomic
systems upon ascending Jacob’s ladder, suggesting a reasonable path for systematic improvement toward higher accuracy (see the
figure). This strategy is more theoretically rigorous and more likely to approach the exact
universal functional. The resulting functionals will also be more reliable for properties
that depend on the electron density.

However, in the near future, this strategy
may not produce functionals that are as
widely applicable for modeling molecular
and condensed phase systems. The challenges are to identify which of the theoretically derived constraints are essential and
to develop functionals that satisfy them
while also producing accurate energies and
geometries. A compromise strategy is to develop empirically parameterized functionals but incorporate the electron density or
related properties, such as dipole moments,
into the databases used in the parameterization procedure.

Given the diversity of the DFT community, which includes theorists, developers,
and practitioners from many fields, all these
strategies will most likely be pursued in parallel. Some strategies will produce functionals for short-term use, whereas others will
focus on long-term solutions. Medvedev et al.
performed a statistical analysis of atomic systems, but an analogous analysis of molecular
systems is also warranted to determine the
generalizability of the conclusions. These issues merit further investigation because, despite the philosophical conundrum discussed
above, most scientists would prefer to obtain
the correct answer for the correct reason. j

REFERENCES AND NOTES

1. M. G. Medvedev, I. S. Bushmarinov, J. Sun, J. P. Perdew, K. A.

Lyssenko, Science 355, 49 (2017).

2. P. Hohenberg, W. Kohn, Phys.Rev. 136, B864 (1964).

3. W.Kohn, L.J.Sham, Phys. Rev. 140,A1133(1965).

4. A.J.Cohen, P.Mori-Sánchez, W. Yang, Chem. Rev. 112,289

(2012).

5. J.P.Perdew, K.Schmidt,in AIP Conference Proceedings,V.

Van Doren, Ed. (AIP Publishing, 2001), vol. 577, pp. 1– 20.

6. H.S. Yu,X.He,D.G. Truhlar, J.Chem. Theory Comput. 12,

1280 (2016).

7. N. Mardirossian, M. Head-Gordon, J. Chem. Phys. 144,

214110 (2016).

8. C. W. Anson et al. , J. Am. Chem. Soc. 138, 4186 (2016).

9. J. Tao et al., Phys. Rev. Lett. 91, 146401 (2003).

10. The figure sho ws the relative density differences with
respect to coupled cluster singles and doubles (CCSD) for
the beryllium atom, as generated with the GAMESS quantum chemistry program ( 11), for four different density
functionals.

11. M. W. Schmidt et al., J. Comput. Chem. 14, 1347 (1993).

ACKNO WLEDGMEN TS

I am grateful for helpful discussions with Y. Yang, M. Pak, K.

Brorsen, and T. Culpitt. This work was supported by the National
Science Foundation under CHE-13-61293.

One means by which cancer cells evade therapies involves their abil- ity to reprogram to a cell type that no longer depends on the cellular pathway being targeted by the treat- ments. Hormone deprivation therapies that suppress androgen receptor (AR)
signaling are the mainstay of treatment for
metastatic prostate cancer. However, prostate cancers can become resistant to this
approach by losing dependence on androgen hormones. On pages 84 and 78 of this
issue, Mu et al. (1) and Ku et al. (2), respectively, contribute to our mechanistic understanding of this remarkable plasticity in
cell identity, which allows cancers to thrive.

Androgens stimulate prostate cancercell growth. The main androgens are tes-tosterone and dihydrotestosterone, whichare synthesized primarily in the testes. De-creasing androgen production or prevent-ing the hormones from acting on prostatecancer cells often makes the tumors shrinkor grow more slowly. However, prostatecancer can adapt to androgen deprivationthrough alterations that restore AR signal-ing and maintain their luminal epithelialadenocarcinoma phenotype, even whenandrogen production is low [referred to ascastration-resistant prostate cancer-adeno(CRPC-adeno)] ( 3). With the developmentof more effective AR-targeting drugs suchas abiraterone and enzalutamide, addi-tional resistance mechanisms are aris-ing. About a quarter of these resistanttumors undergo cellular reprogrammingand acquire a continuum of neuroendo-crine characteristics (CRPC-NE) ( 4, 5). Ge-nomic analyses have shown that CRPC-NEevolves from CRPC-adeno. Most CRPC-NEexpress one or more NE-lineage markers[such as synaptophysin (SYP)], and thereare a range of morphological variants,perhaps reflecting variable differentiationstates. The increased expression of AR andAR-regulated genes is generally reducedin CRPC-NE compared to CRPC-adeno, al-though there is a range of overlap that mayreflect ongoing selection as well as differ-ences in genomics ( 6).

In addition to NE-lineage markers, the
messenger RNA profiles (transcriptomes)
of CRPC-NE patient samples and prostate cancer models have shown increased
expression of genes involved in neuronal
development, such as sex determining region Y box 2 (SOX2), and genes encoding
epigenetic regulators, such as enhancer of
zeste homology 2 (EZH2) and DNA methyl-transferase 1 (DNMT1) ( 6, 7). DNMT1 may
contribute to epigenetic characteristics,
such as DNA methylation patterns, that are
markedly different between CRPC-adeno
and CRPC-NE ( 6). In the most comprehensive genomic analysis of CRPC-NE to
date ( 6), the co-occurrence of alterations
in cell signaling pathways involving the
tumor suppressor proteins retinoblastoma
1 (RB1) and tumor protein 53 (TP53) was
highly enriched in CRPC-NE (~50%) relative to CRPC-adeno (~15%), suggesting the
involvement of these pathways in the selection of CRPC-NE. Mu et al. and Ku et al.
connect the loss of the RB1 and TP53 genes
to lineage plasticity and epigenetic regulation in prostate cancer resistance to androgen deprivation therapy.

Mu et al. addressed the phenotypic consequences of RB1 and TP53 silencing in a
human cell line that overexpresses AR (
LNCaP-AR cells), a model of CRPC-adeno that
is sensitive to the AR antagonist enzalutamide. Silencing both RB1 and TP53,
but neither alone, caused marked enzalutamide resistance in these cells, although
AR activity persisted and remained responsive to enzalutamide. Notably, cells lacking
TP53 and RB1 displayed lineage plasticity,
as indicated by decreased expression of luminal epithelial cell markers and increased
expression of basal epithelial cell and neuroendocrine markers. Moreover, these gene
expression changes occurred within 48
hours of induced depletion of TP53 and RB1
and could be rapidly reversed, indicating a
direct effect rather than selection for cells